Nischarin agonist rilmenidine shows antimetastatic potential in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancer types with a dismal prognosis. Early metastatic dissemination and rich desmoplastic stroma limit therapeutic efficacy, and the discovery of new treatment approaches that will target these obstacles is of great importance. Nischarin (NISCH)/Imidazoline-1 receptor (IR-1) is a potential tumor suppressor, that is involved in the regulation of cell migration, invasion, and cytoskeletal organization. Importantly, several FDA-approved agonists target this receptor. This study aimed to examine the expression of NISCH in PDAC and the effects of its agonists with the intent of drug repurposing. NISCH was expressed in PDAC tumor tissue, in both the epithelial and stromal compartments of tumors, and higher NISCH expression was associated with longer patient survival. Out of the three tested NISCH agonists, rilmenidine was the most potent and could induce cancer cell apoptosis. Rilmenidine treatment induced transcriptional changes in cancer cells associated with so far reported NISCH function and decreased their adhesion and migration in vitro. In CAFs, rilmenidine treatment decreased the expression of activation markers and limited cancer cell-CAF cytokine communication in co-culture. Ultimately, in the in vivo tumor xenograft zebrafish model, rilmenidine reduced the metastatic spread of pancreatic cancer cells. Our results suggest that NISCH agonist rilmenidine is a promising candidate for drug repurposing as an antimetastatic agent in PDAC and that NISCH can be a potential target for the development of new PDAC therapeutics.